The defective gene causing von Recklinghausen neurofibromatosis (NF1), one of the most common inherited disorders affecting the human nervous system, was recently mapped to chromosome 17. We have used additional DNA markers to further narrow and bracket the NF1 defect. A multipoint linkage analysis suggests that the NF1 gene is flanked by D17Z1 on the centromeric side and by EW 207 on the telomeric side of the long arm of chromosome 17. The identification of closely linked flanking markers should allow us to develop a reliable prenatal and presymptomatic diagnostic test for this serious neurological disorder and provides the basis for applying chromosome-specific cloning techniques for the isolation and characterization of the mutant gene.

Von Hippel-Lindau disease (VHL) is an autosomal dominant disorder with inherited susceptibility to various forms of cancer, including hemangioblastomas of the central nervous system, phaeochromocytomas, pancreatic malignancies, and renal cell carcinomas. Renal cell carcinomas constitute a particularly frequent cause of death in this disorder, occurring as bilateral and multifocal tumours, and presenting at an earlier age than in sporadic, non-familial cases of this tumour type. We report here that the VHL gene is linked to the locus encoding the human homologoue of the RAF1 oncogene, which maps to chromosome 3p25 (ref. 4). Crossovers with the VHL locus suggest that the defect responsible for the VHL phenotype is not a mutation in the RAF1 gene itself. An alternative or prior event to oncogene activation in tumour formation may be the inactivation of a putative 'tumour suppressor' which can be associated with both the inherited and sporadic forms of the cancer. Sporadic renal cell carcinomas have previously been associated with the loss of regions on chromosome 3p (refs 5, 6). Consequently, sporadic and VHL-associated forms of renal cell carcinoma might both result from alterations causing loss of function of the same 'tumour suppressor' gene on this chromosome.

Alzheimer's disease is a leading cause of morbidity and mortality among the elderly. Several families have been described in which Alzheimer's disease is caused by an autosomal dominant gene defect. The chromosomal location of this defective gene has been discovered by using genetic linkage to DNA markers on chromosome 21. The localization on chromosome 21 provides an explanation for the occurrence of Alzheimer's disease-like pathology in Down syndrome. Isolation and characterization of the gene at this locus may yield new insights into the nature of the defect causing familial Alzheimer's disease and possibly, into the etiology of all forms of Alzheimer's disease.

Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder of late onset, characterized by progressive motor disturbance, psychological manifestations, and intellectual deterioration. The HD gene has been genetically mapped by linkage to the DNA marker D4S10 , but the exact physical location of the HD defect has remained uncertain. To delineate critical recombination events revealing the physical position of the HD gene, we have identified restriction fragment length polymorphisms for two recently mapped chromosome 4 loci, RAF2 and D4S62 , and determined the pattern of segregation of these markers in both reference and HD pedigrees. Multipoint linkage analysis of the new markers with D4S10 and HD establishes that the HD gene is located in a very small physical region at the tip of the chromosome, bordered by D4S10 and the telomere. A crossover within the D4S10 locus orients this segment on the chromosome, providing the necessary information for efficient application of directional cloning strategies for progressing toward, and eventually isolating, the HD gene.

Bilateral acoustic neurofibromatosis (BANF) is a severe autosomal dominant disorder involving development of multiple tumours of the nervous system including meningiomas, gliomas, neurofibromas and particularly bilateral acoustic neuromas. We have used genetic linkage analysis with DNA markers to establish that the defective gene causing BANF is on chromosome 22, and is therefore distinct from the gene for the von Recklinghausen form of neurofibromatosis, which maps to chromosome 17. Linked DNA markers will be particularly valuable in BANF, facilitating early detection of tumours and thereby permitting more effective surgical intervention. In view of the reported loss of genes on chromosome 22 in meningiomas and acoustic neuromas, the genetic localization of the primary BANF defect strongly supports the concept that the disease locus encodes a 'tumour suppressor' gene. Isolation of this gene should provide insights into the pathogenesis of acoustic neuromas and other nervous system tumours, as well as into the control of proliferation and differentiation of neural crest cells.

von Recklinghausen neurofibromatosis (VRNF) is one of the most common inherited disorders affecting the human nervous system. VRNF is transmitted as an autosomal dominant defect with high penetrance but variable expressivity. The disorder is characterized clinically by hyperpigmented patches of skin (café au lait macules, axillary freckles) and by multiple tumors of peripheral nerve, spinal nerve roots, and brain (neurofibromas, optic gliomas). These tumors can cause disfigurement, paralysis, blindness, and death. We have determined the chromosomal location of the VRNF gene by genetic linkage analysis using DNA markers. The VRNF gene is genetically linked to the locus encoding nerve growth factor receptor, located on the long arm of chromosome 17 in the region 17q12----17q22. However, crossovers with the VRNF locus suggest that a mutation in the nerve growth factor receptor gene itself is unlikely to be the fundamental defect responsible for the VRNF phenotype.

Several recent studies indicate that the von Recklinghausen neurofibromatosis (NF1) gene is located near the centromere of chromosome 17 in some families. However, variable expressivity and a very high mutation rate suggest that defects at several different loci could result in phenotypes categorized as NF1. In order to assess this possibility and to map the NF1 gene more precisely, we have used two polymorphic DNA markers from chromosome 17 to screen several pedigrees for linkage to NF1. We ascertained a large Caucasian pedigree (33 individuals sampled, 17 NF1 affected) as well as eight smaller pedigrees and nuclear families (50 individuals sampled, 30 NF1 affected). Here, we report strong evidence of linkage of NF1 to the centromeric marker D17Z1 (maximum lod = 4.42) and a weaker suggestion of linkage to the ERBA1 oncogene (maximum lod = 0.57), both at a recombination fraction of zero. Since obligate cross-overs with NF1 were not observed for either marker in any of the informative families tested, the possibility of NF1 locus heterogeneity is not supported.

Annals of the New York Academy of SciencesVolume 450, Issue 1 p. 25-31 Genetic Linkage Map for Chromosome 21a JAMES F. GUSELLA, JAMES F. GUSELLA Genetics Unit and Neurology Service Massachusetts General Hospital, and Department of Genetics Harvard Medical School Boston, Massachusetts 02114Search for more papers by this authorRUDOLPH E. TANZI, RUDOLPH E. TANZI Genetics Unit and Neurology Service Massachusetts General Hospital, and Department of Genetics Harvard Medical School Boston, Massachusetts 02114Search for more papers by this authorPAUL C. WATKINS, PAUL C. WATKINS Integrated Genetics, Inc. Framingham, Massachusetts 01701Search for more papers by this authorKERIN T. GIBBONS, KERIN T. GIBBONS Genetics Unit and Neurology Service Massachusetts General Hospital, and Department of Genetics Harvard Medical School Boston, Massachusetts 02114Search for more papers by this authorWENDY J. HOBBS, WENDY J. HOBBS Genetics Unit and Neurology Service Massachusetts General Hospital, and Department of Genetics Harvard Medical School Boston, Massachusetts 02114Search for more papers by this authorANNE G. FARYNIARZ, ANNE G. FARYNIARZ Genetics Unit and Neurology Service Massachusetts General Hospital, and Department of Genetics Harvard Medical School Boston, Massachusetts 02114Search for more papers by this authorSTEVEN T. HEALEY, STEVEN T. HEALEY Genetics Unit and Neurology Service Massachusetts General Hospital, and Department of Genetics Harvard Medical School Boston, Massachusetts 02114Search for more papers by this authorMARY ANNE ANDERSON, MARY ANNE ANDERSON Genetics Unit and Neurology Service Massachusetts General Hospital, and Department of Genetics Harvard Medical School Boston, Massachusetts 02114Search for more papers by this author JAMES F. GUSELLA, JAMES F. GUSELLA Genetics Unit and Neurology Service Massachusetts General Hospital, and Department of Genetics Harvard Medical School Boston, Massachusetts 02114Search for more papers by this authorRUDOLPH E. TANZI, RUDOLPH E. TANZI Genetics Unit and Neurology Service Massachusetts General Hospital, and Department of Genetics Harvard Medical School Boston, Massachusetts 02114Search for more papers by this authorPAUL C. WATKINS, PAUL C. WATKINS Integrated Genetics, Inc. Framingham, Massachusetts 01701Search for more papers by this authorKERIN T. GIBBONS, KERIN T. GIBBONS Genetics Unit and Neurology Service Massachusetts General Hospital, and Department of Genetics Harvard Medical School Boston, Massachusetts 02114Search for more papers by this authorWENDY J. HOBBS, WENDY J. HOBBS Genetics Unit and Neurology Service Massachusetts General Hospital, and Department of Genetics Harvard Medical School Boston, Massachusetts 02114Search for more papers by this authorANNE G. FARYNIARZ, ANNE G. FARYNIARZ Genetics Unit and Neurology Service Massachusetts General Hospital, and Department of Genetics Harvard Medical School Boston, Massachusetts 02114Search for more papers by this authorSTEVEN T. HEALEY, STEVEN T. HEALEY Genetics Unit and Neurology Service Massachusetts General Hospital, and Department of Genetics Harvard Medical School Boston, Massachusetts 02114Search for more papers by this authorMARY ANNE ANDERSON, MARY ANNE ANDERSON Genetics Unit and Neurology Service Massachusetts General Hospital, and Department of Genetics Harvard Medical School Boston, Massachusetts 02114Search for more papers by this author First published: June 1985 https://doi.org/10.1111/j.1749-6632.1985.tb21480.xCitations: 3 † This work was supported in part by Grants NS16367 (Huntington's Disease Center without Walls) and NS20012, from the National Institute for Neurological and Communication Disorders, by a grant from the Hereditary Disease Foundation, and by the Julieanne Dorn Fund for Neurological Research. AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Citing Literature Volume450, Issue1Adenosine Molecular Structure of the Number 21 chromosome and Down SyndromeJune 1985Pages 25-31 RelatedInformation